Self tolerance induction in the thymus is known to delete T cells expressing certain V beta TCR molecules. In particular, V beta 17a+ and V beta 11+ T cells are selectively deleted in mice expressing H-2 I-E molecules. Although this finding implies that V beta 17a+ and V beta 11+ T cells have specificity for self I-E molecules, studies with V beta 11+ hybridomas prepared from mature lymphocytes taken from I-E- mice have shown that the vast majority of these hybridomas do not display I-E alloreactivity, at least in vitro. To examine whether V beta 11+ T cells are capable of reacting to I-E antigens in vivo, normal unprimed T cells from I-E- B10.A(4R) mice were transferred to irradiated I-E+ B10.A(2R) hosts and harvested from thoracic duct lymph of the recipients at various intervals. The donor T cells recovered in early lymph collections showed no reactivity to the I-E antigens of the host in vitro, presumably as a reflection of selective sequestration of the host-reactive cells in the lymphoid organs. Significantly, the disappearance of functional host-reactive cells from TDL was paralleled by a 90-95% reduction of V beta 11+ CD4+ cells. Blast cells were rare in early lymph collections but accounted for nearly all of the lymph-borne cells by day 3 after transfer. These blast cell populations contained a surprisingly high proportion of V beta 11+ cells, i.e., up to 25% in some experiments. Interestingly, the enrichment for V beta 11+ cells in the blast populations applied to CD8+ cells as well as to CD4+ cells. Collectively, the data suggest that in marked contrast to the failure of V beta 11+ cells to respond to I-E antigens in vitro, a high proportion of normal resting V beta 11+ cells are capable of reacting to I-E alloantigens in vivo.